2,3,4,5-tetrahydro-1h-3-benzazepine-7,8-diones

ABSTRACT

Novel benzazepine derivatives having central and peripheral dopaminergic activity useful in treating Parkinson&#39;s and cardiovascular diseases. The compounds have additional use as intermediates for the synthesis of other benzazepines with similar useful properties. The 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione derivatives are particularly useful.

This invention relates to novel derivatives of1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines having valuablepharmacodynamic activity. More specifically, these compounds arestimulants of the central and peripheral dopamine receptors and areuseful in the treatment of Parkinson's and cardiovascular diseases.

Further, the compounds have particular utility as intermediates for thesynthesis of other benzazepines with similar useful properties.Advantageously the compounds of this invention can be employed in thepreparation of loweralkylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.For example, the 7,8-dione of Formula 1 is reacted with the desiredmercaptan (RSH) in a suitable inert organic solvent such as an alcoholicsolvent, methanol or ethanol to give a mixture of the 6- and 9-loweralkylthio containing isomers which can be easily separated into the 6and 9 isomers by methods known to the art. If either the 6 or 9 positionis occupied by a group the adding group will go to the unoccupiedposition.

The compounds of this invention can also serve as intermediates for thesynthesis of 6-bromo or 6- and9-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.The dione of Formula 1 is reacted with hydrogen bromide or hydrogenchloride by methods similar to the mercaptan addition in an inertorganic solvent such as, for example, methylene chloride, to yield6-bromo or a mixture of 6- and 9-chloro containing isomers. The mixtureof isomers can be easily separated into the 6 or 9 isomer by methodsknown to the art.

The compounds of this invention are represented by the following generalstructural formula: ##STR1## IN WHICH:

R is hydrogen or halo, especially chloro, fluoro or bromo;

R₁ is lower alkyl having from 1 to 5 carbon atoms, lower alkanoyl havingfrom 1 to 5 carbon atoms such as formyl, acetyl or trifluoroacetyl,benzyl, phenethyl, carbobenzyloxy or hydroxyethyl; and

R₂ is thienyl, methylthienyl, furyl, phenyl or phenyl which isoptionally substituted with a lower alkyl having from 1 to 5 carbonatoms preferably methyl, a halo such as fluoro, chloro, bromo or iodo, alower alkoxy having from 1 to 4 carbon atoms preferably methoxy, hydroxyor methylthio.

Preferred compounds of this invention are represented by Formula 1 abovewhen R is hydrogen, R₁ is hydrogen or methyl, and R₂ is phenyl or monosubstituted phenyl. A particularly advantageous compound of Formula 1 is1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione.

The pharmaceutically acceptable acid addition salts having the utilityof the free bases of Formula 1, prepared by methods well known to theart, are formed with both inorganic or organic acids, for example:maleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicyclic, methanesulfonic, ethanedisulfonic, acetic,oxalic, propionic, tartaric, salicylic, citric, gluconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, hydrochloric, hydrobromic, sulfuric,cyclohexylsulfamic, phosphoric and nitric acids. Similarly thequaternary salts include those prepared from inorganic halides such asmethyl iodide, ethyl iodide, benzyl chloride and the like.

1-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines have been described inU.S. Pat. No. 3,393,192; British patent specification No. 1,118,688; andSwiss Pat. No. 555,831, including general methods of preparation.However, these references disclose no 7,8-dione compounds falling withinthe scope of Formula 1 hereinabove. In addition there is no disclosureof the dopaminergic properties of such compounds and their utility inthe biological or chemical methods of this invention. These referencesdo disclose 7,8-dihydroxy substituted 1-phenyl-3-benzazepines andvarious intermediates therefor, some of which serve as startingmaterials for preparing the compounds of this invention.

It will be obvious to one skilled in the art that the compounds ofFormula 1 may be present as diastereoisomers which may be resolved intod and l optical isomers. Resolution of the optical isomers may beconveniently accomplished by fractional crystallization of their saltswith optically active acids from appropriate solvents. Unless otherwisespecified herein or in the claims, it is intended to include allisomers, whether separated or mixtures thereof. Where isomers areseparated, the desired pharmacological activity will usually predominatein one of the isomers.

The compounds of Formula 1 may be prepared by oxidation of a7,8-dihydroxy substituted benzazepine of the formula: ##STR2## in which:

R, R₁ and R₂ are described above.

The oxidation is preferably carried out with2,3-dichloro-5,6-dicyano-1,4 benzoquinone in an inert organic solvent inwhich the reactants are soluble such as methanol ethanol usually in thecold at about 0°-5° C. until the oxidation is complete. A number ofother mild oxidizing agents known to convert catechols to o-quinones maybe employed such as, for example, silver oxide, ceric ammonium nitrate,chloranil, silver carbonate, or succinidodimethylsulfonium cation.

The 7,8-dihydroxy substituted starting materials are either known to theart or are prepared by known methods such as the cyclization reactionsdescribed in U.S. Pat. Nos. 3,393,192 and 4,011,319.

The compounds of Formula 1 and their nontoxic pharmaceuticallyacceptable addition salts have a dopaminergic effect. They have a dualeffect on dopamine receptors in the central nervous system notably thebrain as well as on peripheral dopamine receptors such as thoseaffecting the peripheral cardiovascular system.

The latter effect results in increased renal blood flow with a resultinghypotensive effect. It is often measured by administering the compoundby infusion i.v. incrementally at 5 minute intervals to the anesthetizednormotensive dog with measurement of various cardiovascular parameters.The effect on renal vasculator resistance can be calculated from anychange in renal blood flow and arterial blood pressure. The effect isquantified as an ED₁₅ value which is the cumulative dose which producesa 15% decrease in renal vascular resistance ##EQU1##

The compounds of Formula 1 have also been demonstrated as havingantiParkinsonism activity due to central dopaminergic activity asdemonstrated by employing a modified standard animal pharmacologicaltest procedure reported by Ungerstedt et al., in Brain Research 24,1970, 485-493. This procedure is based on a drug induced rotation ofrats having extensive unilateral lesions of the substantia nigra.Briefly, the test comprises the quantitative recording of rotationalbehavior in rats in which 6-hydroxydopamine lesions of the nigrostriataldopamine system have been produced. A unilateral brain lesion in theleft substantia nigra causes the dopamine receptor in the left caudateto become hypersensitive following the resulting degeneration of thenigral cell bodies. These lesions destroy the source of theneurotransmitter dopamine in the caudate but leave the caudate cellbodies and their dopamine receptors intact. Activation of thesereceptors by drugs which produce contralateral rotation, with respect tothe lesioned side of the brain, is used as a measure of centraldopaminergic activity of the drug.

Compounds which are known to be clinically effective in controllingParkinsonism, such as, for example, L-dopa and apomorphine, are alsoeffective in this rat turning model. These compounds directly activatethe dopamine receptors and cause contralateral rotation of the lesionedrat.

Rotational activity is defined as the ability of a compound to produce500 contralateral rotations during a two-hour period afteradministration, usually intraperitoneally. The dose corresponding to 500contralateral rotations per 2 hours is obtained and assigned as theRD₅₀₀ value.

An advantageous compound of Formula 1,1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione had an ED₁₅ of280 mcg./kg. when tested for renal vasodilator activity and an RD₅₀₀ of2.2 mg./kg. when tested in the above modified Ungerstedt test.

The compositions of this invention are prepared in conventional dosageunit forms by incorporating a compound of Formula 1 of apharmaceutically acceptable salt thereof, in a nontoxic amountsufficient to stimulate central and peripheral dopamine receptors in ananimal, with a nontoxic pharmaceutical carrier according to acceptedprocedures. Preferably the compositions will contain the activeingredient in an active but nontoxic amount selected from about 20 mg.to about 1000 mg. of active ingredient per dosage unit.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly the carrier or diluent may includeany time delay material well known to the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampul or for i.v.infusion, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingredients as appropriate to the desired end product.

The method of producing dopaminergic activity in accordance with thisinvention comprises administering internally to an animal in need ofsuch activity a compound of Formula 1 or a pharmaceutically acceptablesalt thereof, usually combined with a pharmaceutical carrier, in anontoxic amount sufficient to stimulate said peripheral dopaminereceptors. The active ingredient will be administered preferably in adosage unit, in an active, nontoxic quantity selected from about 20 mg.to about 1000 mg. of the parent chemical of Formula 1. The route ofadministration may be orally or parenterally, the oral route beingpreferred. Advantageously equal doses will be administered three times aday with the daily dosage regimen being selected from about 60 mg. toabout 3000 mg. For administration by i.v. infusion, for example over a10 to 30 minute period, a total dose selected from about 0.5 mg. toabout 50 mg. will be administered. When the method described above iscarried out stimulation of peripheral dopamine receptors is producedwith a minimum of side effects.

The following examples illustrate the preparation of specific compoundsand pharmaceutical compositions having dopaminergic activity,specifically antiParkinsonism and cardiovascular activity. However,these examples should not be construed as a limitation of the inventionsince other variations will be obvious to those skilled in the art.

In the following examples the infrared absorption maxima for thecarbonyl groups of the 7,8-diones were measured in nujol mulls and arereported in microns (μ). The positions of the C-6 and C-9 protons in thenmr spectra of the 7,8-diones were measured at 60 MH₂ in CDCl₃ -DMSO,D₆(1:1) and are reported in delta units (δ).

EXAMPLE 1

To a suspension of 34 g. (0.101 mole) of7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromidein 275 ml. of methanol was added a solution of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (25.2 g. 0.111 mole) in 125ml. of methanol. The addition was carried out rapidly with stirring at0° under an argon atmosphere. After stirring at 0° for 1 hour, thereaction mixture was filtered and the precipitate washed with coldmethanol (75 ml), ethyl acetate (100 ml) and then diethyl ether (100ml). After drying at room temperature under vacuum1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine-7,8-dione hydrobromide wasobtained, m.p. 164°-165° (dec); ir:6.00, 6.08; nmr:6.38 (6H), 5.42 (9H).

EXAMPLE 2

Sodium hydride (57%, 4.84 g., 0.115 mole) previously washed with hexaneis stirred with 70 ml. of dimethylsulfoxide at 65°-70° C. for 2 hoursunder dry argon. The mixture is diluted with 70 ml. of drytetrahydrofuran, cooled to -5° C. and 23.5 g. (0.115 mole) oftrimethylsulfonium iodide in 100 ml. of dry dimethyl sulfoxide is addedover a period of several minutes. After stirring for one minute, 11.9 g.(0.0926 mole) of m-tolualdehyde is added at a moderate rate maintainingthe temperature at 0° to -5° C. The mixture is stirred at 0° C. for 5minutes and at room temperature for 1 hour, diluted with 500 ml. ofice-water and extracted with ether. The extract is washed with saturatedsodium chloride solution, dried and evaporated to an oil,m-methylstyrene oxide.

A mixture of 14.5 g. (0.0797 mole) of 3,4-dimethoxyphenethylamine and10.7 g. (0.0797 mole) of m-methylstyrene oxide is stirred at 100° C.under argon for 16 hours and then diluted with benzene. Cooling in iceprecipitatesN-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(3-methylphenyl)ethylamine,m.p. 95.5°-97° C.

The above prepared ethylamine (9.6 g., 0.0304 mole) is refluxed in 65ml. of 48% hydrobromic acid for 2 hours under argon. Cooling yields theproduct7,8-dihydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 108°-110° C.

The above compound is reacted with2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol as in Example 1 togive 1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide.

Following the above procedure and substituting o-tolualdehyde form-tolualdehyde as a starting material yields1-(2-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione;ir:6.05; nmr:6.39 (6H), 5.25 (9H).

EXAMPLE 3

A mixture of 42.0 g. of 57% sodium hydride dispersed in oil and 700 ml.of dimethyl sulfoxide is stirred at 70°-75° C. for 1 to 11/2 hours. Thesolution is diluted with 700 ml. of dry tetrahydrofuran and cooled to 0°C., under nitrogen. A 200 g. (1.0 mole) sample of trimethylsulfoniumiodide is added in portions, maintaining the temperature between 0°-5°C. The mixture is stirred for 15 minutes and then a solution of 70.4 g.(0.50 mole) of m-chlorobenzaldehyde in 300 ml. of dry tetrahydrofuran isadded dropwise. The resulting mixture is stirred at room temperature for4 hours, poured into water and extracted with ether. The extract iswashed with brine, dried and evaporated in vacuo to leavem-chlorostyrene oxide.

A solution of 27.1 g. (0.1 mole) ofN-benzyl-3,4-dimethoxyphenylethylamine and 23.3 g. (0.15 mole) ofm-chlorostyrene oxide in 500 ml. of methanol is stirred and refluxedovernight. The methanol is removed in vacuo and the residualN-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(3-chlorophenyl)ethylamineis reduced without further purification. This sample (0.01 mole) isdissolved in ether, acidified with ethereal hydrogen chloride andhydrochloride precipitates. The latter is dissolved in 90 ml. ofmethanol, the solution is added to a mixture of 0.5 g. ofpalladium-on-carbon in 10 ml. of ethyl acetate and the mixture ishydrogenated at room temperature for 90 minutes at 60 psi. The reactionmixture is filtered and the filtrate evaporated in vacuo to yieldN-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(3-chlorophenyl)ethylaminehydrochloride, m.p. 155°-157.5° C.

A solution of 6.0 g. (0.0161 mole) of the above prepared amine in 250ml. of 48% hydrobromic acid is stirred and refluxed for 3 hours. Thereaction mixture is evaporated to give1-(3-chlorophenyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

This compound is oxidized using the benzoquinone as in Example 1 toyield 1-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide; ir:6.01; nmr:6.40 (6H), 5.47 (9H).

EXAMPLE 4

A mixture of 4.32 g. (0.0154 mole) of7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 mole ofn-butyl bromide and 0.02 mole of potassium hydroxide is dissolved in 120ml. of dry methanol and refluxed for 48 hours. The reaction mixture isevaporated to dryness, taken up in ethyl acetate and filtered to removeinorganic salts. The filtrate is washed with water, dried and evaporatedto give3-n-butyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine asan oil.

The 3-n-butyl benzazepine (0.0107 mole) is dissolved in 120 ml. of drymethylene chloride and 0.032 mole of boron tribromide is added dropwiseat -10° C. The solution is warmed to room temperature and stirred fortwo hours. The excess boron tribromide is destroyed with methanol addeddropwise with ice-cooling. The cold solution is refluxed on the steambath to remove hydrogen bromide and then evaporated to yield3-n-butyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepinehydrobromide, m.p. 231°-234° C.

The above compound is oxidized with the benzoquinone as in Example 1 togive 3-n-butyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine-7,8-dionehydrobromide.

EXAMPLE 5

A 3.3 g. (0.019 mole) quantity of7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (free base)was slurried in 40 ml. of dry acetone and 4.0 g. of anhydrous potassiumcarbonate was added. The mixture was stirred under nitrogen, a smallamount of ascorbic acid was added as antioxidant and the mixture chilledto 0° and 1.57 g. (0.0129 mole) of allyl bromide was added. The mixturewas stirred two to three hours in the cold and allowed to warm toambient temperature and stirred an additional twelve hours. The mixturewas then heated to reflux for thirty minutes and cooled, poured intowater and extracted with three portions of ethyl acetate. Concentrationof the combined extracts gave 2.7 g. of solid (71% crude yield). Thiswas taken up in boiling ether and the solution allowed to stand forseveral hours. Filtration removed a small amount of precipitate andethereal hydrogen chloride was then added to the filtrate to precipitatethe hydrochloride salt which was isolated as an amorphous butnon-hygroscopic solid, 2.0 g. on filtration and drying. Trituration ofthe solid with hot ethyl acetate followed by recrystallization fromethanol-ethyl acetate gave 0.85 g. of crystalline3-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 232°-234° (dec.).

This compound is reacted with quinone as in Example 1 to give3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrochloride.

Substituting phenethyl bromide in the above reaction gives the3-phenethyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione.

Further substituting the 3-methyl and 3-benzyl compounds and thenoxidizing them with the benzoquinone of Example 1 gives3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrochloride; ir:6.01; nmr:6.41 (6H), 5.37 (9H); and3-benzyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione.

EXAMPLE 6

A solution of 7.10 g. (18.6 mole) of7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromidein 120 ml. of aqueous dimethyl-formamide at 0° under an argon atmosphereis basified to pH 10.0 with 10% sodium hydroxide solution. To this coldmixture is added 13.0 g. (76 mole) of carbobenzyloxy chloride in smallportions over 15 minutes with concomitant addition of 10% alkali so asto maintain a pH of 10 to 10.5. The reaction is allowed to warm to roomtemperature after stirring at 0° for 11/2 hours. The mixture is dilutedwith saturated salt and extracted with three portions of ethyl acetate.The combined organic extract is backwashed twice with saturated salt.The dried extract is concentrated in vacuo and heated at 75°/0.1 mm Hgto remove any benzyl alcohol to yield7,8-dihydroxy-N-carbobenzyloxy-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine.

A solution of the above benzazepine (16.7 g.) in 150 ml. of ethylacetate is stirred with silver oxide (36.6 g.) and anhydrous sodiumsulfate (11.4 g.) under an argon atmosphere. The mixture is filtered andevaporated to giveN-carbobenzyloxy-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine-7,8-dione.

EXAMPLE 7

7,8-Dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (5.0 g.) issuspended in 50 ml. of benzene. Trifluoroacetic anhydride (15 g.) isadded dropwise rapidly. The solution is stirred an additional hour andthen the volatiles are stripped off, leaving theN,O.O-tris-trifluoroacetyl derivatives. This is added directly to 50 ml.of methanol and hydrogen chloride gas is bubbled in for a few minutes.The reaction is stirred for 2 hours and the solvent stripped off,leaving a residue of7,8-dihydroxy-1-phenyl-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

The above compound is oxidized with silver oxide following the procedureof Example 6 to yield the 7,8-dione derivative.

EXAMPLE 8

A 3.7 g. (0.0145 mole) sample of7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base wasslurried in 25 ml. of acetone and 0.07 g. (0.016 mole, 10% excess) ofethylene oxide was added and the mixture placed in a pressure bottle andstirred at ambient temperature for 40 hours. The reaction mixture washeated to 60°-80° for 30 minutes, cooled and filtered. Concentration ofthe filtrate gave 4.5 g. of crystalline solid. This was taken up inethyl acetate, reprecipitated by the addition of ether and converted toits hydrochloride salt by solution in ethanol, addition of etherealhydrogen chloride and precipitation of the salt by additional ether togive 3.0 g. (yield 60%) on drying. Recrystallization from ethanol-ethergave 1.9 g. (yield 38%), m.p. 136°-137° of7,8-dihydroxy-3-(2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride.

The 2-hydroxyethyl compound (1.5 g.) is reacted with2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol as in Example 1 togive3-(2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrochloride.

EXAMPLE 9

A suspension of 4.84 g. of sodium hydride (57% mineral oil dispersion)in 70 ml. of dry dimethyl sulfoxide is heated at about 65° C. underargon with stirring for 1 hour. Dry tetrahydrofuran (75 ml.) is addedand the resulting solution is cooled to -5° C. Trimethylsulfonium iodide(19 g., 92.8 mmole) is added very slowly and stirring is continued forabout 5 minutes. A solution of 12.6 g. (92.8 mmole) ofp-methoxybenzaldehyde in 120 ml. of tetrahydrofuran is added and thetemperature is maintained at -5° C. After addition is completed themixture is allowed to warm to room temperature, poured into water andextracted with ether. The extract is washed with saturated sodiumchloride solution, dried and evaporated to give p-methoxystyrene oxide.

A mixture of 16 g. (88 mmole) of 3,4-dimethoxyphenylethylamine and 13.5g. (88 mmole) of p-methoxystyrene oxide is heated with stirring underargon on a steam bath overnight. A sample is withdrawn from the reactionmixture and chromatographed on a silica column, eluting with benzeneethyl acetate to isolate the pure product in crystalline form. To theremainder of the reaction mixture is added 100 ml. of ethylacetate-hexane (1:1) and seeded with the crystalline product, withstirring and chilling. Filtration furnishes the productN-[2-(3,4-dimethoxyphenyl)-ethyl]-2-hydroxy-2-(4-methoxyphenyl)ethylamine,m.p. 92° C.

A solution of 4.4 g. (13.3 mmole) of the above prepared ethylamine in 20ml. of 48% hydrobromic acid is heated at reflux under argon for twohours. Cooling precipitates7,8-dihydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 287°-289° C.

The compound is oxidized using the 1,4-benzoquinone as in Example 1 togive 1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide.

Following the above procedure and substituting m-methoxybenzaldehyde forp-methoxybenzaldehyde as a starting material yielded1-(3-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide; ir:6.03; nmr:6.38 (6H), 5.60 (9H).

EXAMPLE 10

A mixture of 8.9 g. (40 mmoles) of1-hydroxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine and 5 ml. ofthiophene in 45 ml. of trifluoroacetic is treated under argon at roomtemperature overnight. The volatiles are stripped off and the residuedissolved in 250 ml. of 3N hydrochloric acid. This acidic solution iswashed with ether, basified with concentrated ammonium and extractedthree times with ethyl acetate. The extracts are combined, washed withsaturated brine and dried anhydrous potassium carbonate. The dryingagent and solvent are removed to give1-(2'-thienyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.

3.5 grams (12 mmoles) of1-(2'-thienyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine isdissolved in 60 ml. of methylene chloride and cooled to -12° by means ofa methanol-ice bath, and 6 ml. (62 mmoles) boron tribromide is addeddropwise. The resulting solution is stirred at room temperature for 1.5hours and then evaporated to a brown residue under reduced pressure. Theresidue is cooled in ice and treated slowly with methanol. The methanolis evaporated at room temperature under reduced pressure. The residue istreated with methanol again and stripped under reduced pressure in a 50°hot-water bath. This treatment is repeated 3 times. The final residue iseither chromatographed on a silica column eluted with 9:1chloroform/methanol or dissolved in water. Any undissolved material isfiltered off and the aqueous filtrate lyophilized to give pure1-(2'-thienyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-3-1H-benzazepinehydrobromide salt, m.p. 239°-240° (dec.).

The above compound is oxidized with the benzoquinone of Example 1 togive 1-(2'-thienyl)-2,3,4,5-tetrahydro-3-1H-benzazepine-7,8-dione.

EXAMPLE 11

Substituting 2-methyl-thiophene for thiophene as a starting material inand following the procedure of Example 10 yields1-(5'-methyl-2'-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione;ir:6.00; nmr:6.35 (6H); 5.70 (9H).

In the same way using furan as a starting material in Example 10 yields1-(2'-furyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione.

EXAMPLE 12

A mixture of 11 g. (0.26 mole) of 57% sodium hydride and 183 ml. of drydimethylsulfoxide was heated at 61°-66° for 2 hours. The mixture wascooled to room temperature and diluted with 183 ml. of drytetrahydrofuran. The mixture was again cooled to -3° C. and a solutionof 53.45 g. (0.26 mole) of trimethyl sulfonium iodide in 183 ml. of drydimethylsulfoxide was added dropwise. Stirring was continued for 5minutes and 19.2 g. (0.126 mole) of O-(methylthio)benzaldehyde in 20 ml.of dimethylsulfoxide was added with stirring overnight. The reaction wasquenched on ice water and extracted with three 300 ml. portions of 1:1benzene-ether. The combined extract was dried over magnesium sulfate andconcentrated in vacuo to give O-(methylthio)phenylethylene epoxide.

The above epoxide (0.126 mole) was heated with 22.84 g. (0.126 mole) ofhomoveratrylamine at 110° for 2 hours under nitrogen at which time thereaction set solid. Thin layer chromatogram showed complete conversionand the product was crystallized from hot methanol and set overnight ina freezer. The mixture was filtered, washed with ether and air dried togive 20.0 g. of N-[β-hydroxy-O-(methylthio)phenethyl]homoveratrylamineas white needles, m.p. 140°-142° C.

A solution of 5.0 g. (0.014 mole) of the amine in 50 ml. of 48% hydrogenbromide was heated at 80°-100° under nitrogen for 1 hour. The mixturewas diluted with 100 ml. of water and concentrated in vacuo to yield abrown syrup. The syrup was diluted with 200 ml. of 50% isopropanol,treated with Darco and concentrated once again. The residual syrup wasstripped several times from absolute ethanol and then triturated under200 ml. of isopropanol, stirred in the cold and then refrigeratedovernight. The solvent was decanted and slurred in ether. This wasrepeated and the solvent was pumped off at 1 min. Hg. The resultingpowder became gummy. The material was peracetylated in pyridine,chromatographed on silica to yield1-(2-methylthiophenyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

The above benzazepine compound is reacted with2,3-dichloro-5,6-dicyano-1,4 benzoquinone in methanol as in Example 1 togive1-(2-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide; ir:5.93, 6.01; nmr:6.39 (6H), 5.25 (9H).

Following the above procedure and substitutingp-(methylthio)benzaldehyde as a starting material foro-(methylthio)benzaldehyde yielded1-(4-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide; ir:6.00; nmr:6.37 (6H), 5.46 (9H).

EXAMPLE 13

Isovanillin (200 g. 1.32 mole) was suspended in 1200 cc chloroform.Chlorine (103 g., 1.45 mole) was added by means of three 500 cc portionsof carbon tetrachloride, in which it was dissolved. The suspension wasstirred vigorously during the addition and the reaction was kept around25° by a water bath. The suspension was stirred for 22 minutes after thecompletion of the addition of chlorine. The precipitate was filtered andcrystallized from methanol, then recrystallized from isopropanol/ethylacetate. Yield 98.7 g. (40%, m.p. 204°-206°) on2-chloro-3-hydroxy-4-methoxybenzaldehyde.

The aldehyde product (189.3 g., 1.02 mole) was suspended in 1 liter ofdry dimethylformamide, 350 g. of potassium carbonate was added. 145 cc.(124 g., 1.54 mole) of dimethyl sulfate was added dropwise over a 20minute period. After the addition the reaction was heated on the steambath for 5 minutes. 70 cc. of water were added and the reaction wasagain heated for 5 minutes on the steam bath. The reaction was thenpoured into ice water and the precipitate was collected. It wascrystallized from acetic acid/water (800 cc.-50cc.). A second crop wasobtained from the mother liquor. Yield 180 g. (90%) of2-chloro-3,4-dimethoxybenzaldehyde after drying, m.p. 69°-70°.

The dimethoxybenzaldehyde (180 g., 0.9 mole) was dissolved in 500 cc.warm acetic acid. 61 g. (0.8 mole) of ammonium acetate was added,followed by 160 cc. of nitromethane. The reaction was heated vigorouslyon the steam bath for 3 hours. Water was then added to the cloud point,while still heating, and the solution was cooled and scratched. Theβ-nitrostyrene began to oil out and then crystallized. The solution wascooled. The yellow crystals were collected and dried in a vacuum oven.Yield 175 g. (80% m.p. 88°-91°) of2-chloro-3,4-dimethoxy-β-nitrostyrene.

The nitrostyrene (80 g., 0.33 mole) was dissolved in 800 cc. of drytetrahydrofuran. Lithium aluminum hydride, as a 3.7 M solution (260 cc.,0.36 mole), was put in a 5 liter 3 neck flask which had been dried andflushed with argon. It was diluted with 500 cc. of dry ether. Thesolution of the nitrostyrene was added in a thin stream. The flask wascooled in an ice bath so that the heat of reaction caused a gentlereflux of the ether. After addition, the reaction was refluxed one hour,then worked up by adding 36 cc. of water, 36 cc. of 10% sodium hydroxideand 108 cc. of water sequentially and carefully, while cooling thereaction in ice.

The precipitate was collected, washed well with ethyl ether anddiscarded. The ether-tetrahydrofuran mixture was evaporated.

The above reaction was repeated on 83 g. of nitrostyrene. The two crudeproducts were combined and distilled at 0.5 mm to collect at 142°-155°the product containing fraction which was pure2-(2-chloro-3,4-dimethoxyphenyl)ethylamine by t.l.c. (80 g.).

The phenethylamine (25.7 g., 0.12 mole) was heated to 115° in an oilbath. Styrene oxide (14.4 g., 0.12 mole) was added and the reaction washeated for 1 hour. After cooling to ˜30°, 2:1 petroleum ether/acetonewas added to dissolve the oil;N-[(2-hydroxy-2-phenylethyl)]-N-[2-(2'-chloro-3',4'-dimethoxyphenyl)ethyl]amine,crystallized out in 37% yield (15 g.) m.p. 100°-101°.

The hydroxyphenethylamine (15 g. (0.0445 mole) was dissolved in 60 cc.of trifluoroacetic acid and 4.05 cc. of concentrated sulfuric acid wasadded. The reaction was refluxed 2 hours. After cooling most of thetrifluoroacetic acid was stripped off and the residue was poured intowater. It was made basic with 10% sodium hydroxide and was extractedwith ether twice. The ether was dried, and as it was evaporated, thesolid separated which was collected; m.p. 115°-121°, 6.0 g. of6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Theremaining ether was treated with ethereal hydrogen chloride and thehydrochloride salt precipitated; yield 3.2 g., total 62% m.p. 234°-236°.The dimethoxy derivative was converted to6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide using boron tribromide in a 77% yield, m.p. 259°-260°.

The above compound is reacted with the benzoquinone as in Example 1 toyield 6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide.

EXAMPLE 14

7,8-Dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (280 g., 0.75mole) was dissolved in 1700 cc. of acetic acid. Bromine (280 g., 1.75mole) was added in a thin stream. The reaction was stirred for 2 hours.The precipitate, which formed after 1 hour, was collected and washedwith ether. It was dissolved in boiling methanol and acetone was addedto destroy the bromine excess.6-Bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide was allowed to crystallize from the methanol and a secondcrop was obtained by adding ether to the mother liquor. Yield 298 g.,77% m.p. 236°-238°. This bromination may be applied to any 7,8-dialkoxyor alkanoyloxybenzazepine having a free 6-position.

The hydrobromide was shaken in a mixture of excess 10% sodium hydroxideand methylene chloride. The organic layer was separated, dried andevaporated to give a solid base which was crystallized fromtoluene-hexane; m.p. 125°-128°, yield 238 g. (97%).

The base (12 g., 0.033 mole) was dissolved in 200 cc. of methylenechloride and was cooled to -15° C. Boron tribromide (15.4 cc., 16 mole)was added cautiously. The reaction was allowed to run at roomtemperature for 2 hours. The solvent was stripped off and the flask wascooled to -15°. Dry methanol was added to destroy the boron tribromidecomplexes. It was then stripped off. The residue was crystallized fromwater, then boiled in acetonitrile to aid in the drying of the compound.Yield of6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide; 10.26 g. (75%), m.p. 240°-242° after vacuum drying.

The 6-bromo compound is oxidized using the benzoquinone as in Example 1to yield 6-bromo-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide.

EXAMPLE 15

To a stirred suspension of1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione (5 g., 0.015mole) in 150 ml. of methanol was rapidly bubbled an excess of methylmercaptan. The orange quinone quickly dissolved to give a pale yellowsolution which was evaporated to a residue which was a mixture of7,8-dihydroxy-6-methylthio and9-methylthio-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

A mixture of the isomers (3.3 g.) was dissolved in 3.2 ml. of methanoland diluted to 80 ml. with chloroform. This solution was applied to asilica gel column (100 g., 4.5 × 15 cm) and eluted with a lineargradient composed of chloroform containing an increasing concentrationof methanol (1000 ml., 5 to 20% methanol). The 6-isomer was eluted firstfollowed by a mixture of 6- and 9-isomers and then the 9-isomer.Fractions containing the pure 6-isomer were combined and evaporated to aresidue (1.4 g.) which was crystallized from ethanol-ethyl acetate togive 0.64 l g. (0.0017 mole, 11%), m.p. 258° (dec.).

Anal. Calc'd for C₁₇ H₁₉ NO₂ S.HBr: C, 53.41; H, 5.27; N, 3.66; S, 8.39.Found: C, 53.41; H, 5.10; N, 3.55; S, 8.64.

Fractions containing the pure 9-isomer were evaporated to a residue andcombined with the 2.2 g. obtained by direct crystallization.Recrystallization from methanol-ethyl acetate gave the pure 9-isomer(1.25 g., 0.0034 mole, 22%), m.p. 270° (dec.).

Anal. Calc'd for C₁₇ H₁₉ NO₂ S.HBr: C, 53.41; H, 5.27; N, 3.66; S, 8.39.Found: C, 53.15; H, 5.33; N, 3.58; S, 8.24.

EXAMPLE 16

Under an argon atmosphere dry hydrogen chloride was bubbled into astirred suspension of1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrochloride (1g.) in 50 ml. of methylene chloride. After the initial color of theprecipitate changed to an off-white color, the suspension was chilledand filtered to give a mixture of 6-chloro and 9-chloro isomers. Theseisomers were separated by chromatography on silica gel as described inExample 15. The separated isomers were recrystallized from methanolethylacetate to yield respectively6-chloro-1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide and9-chloro-1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

EXAMPLE 17

Under an argon atmosphere dry halogen bromide was bubbled into a stirredsolution of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dionehydrobromide (1.2 g.) in 60 ml. of methylene chloride. After theoriginal orange color of the dione disappeared the product was filteredand recrystallized from methanol-ethyl acetate to yield the desired6-bromo-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

EXAMPLE 18

    ______________________________________                                        Ingredients           Mg. per Capsule                                         ______________________________________                                        1-phenyl-2,3,4,5-tetrahydro-1H-                                               3-benzazepine-7,8-dione                                                                             125 (free base)                                         Magnesium Stearate     2                                                      Lactose               200                                                     ______________________________________                                    

The above ingredients are thoroughly mixed and placed into hard gelatincapsules.

EXAMPLE 19

    ______________________________________                                        Ingredients           Mg. per Tablet                                          ______________________________________                                        1-(3-methylphenyl)-2,3,4,5-                                                   tetrahydro-1H-3-benzazepine-                                                  7,8-dione hydrobromide                                                                              200 (free base)                                         Corn Starch            50                                                     Polyvinyl pyrrolidone  12                                                     Magnesium Stearate     3                                                      ______________________________________                                    

A portion (30 mg.) of the corn starch and benzazepine are mixed andgranulated with the polyvinyl pyrrolidone. The granules are dried, mixedwith the remaining starch and magnesium stearate and compressed intotablets.

The capsules and tablets as prepared in Examples 18 and 19 areadministered orally to an animal including a human requiring stimulationof dopamine receptors within the dose ranges set forth hereinabove.Similarly other compounds of Formula 1 or the other examples can beformulated in the same manner to give pharmaceutical compositions usefulin the methods of this invention.

What is claimed is:
 1. A compound of the formula: ##STR3## in which: Ris hydrogen or halo;R₁ is lower alkyl having from 1 to 5 carbon atoms,lower alkanoyl having from 1 to 5 carbon atoms, benzyl, phenethyl,carbobenzyloxy, or hydroxyethyl; and R₂ is phenyl, or phenyl which isoptionally substituted with a lower alkyl having from 1 to 5 carbonatoms, halo, lower alkoxy having from 1 to 4 carbon atoms, hydroxy orthiomethyl;and the pharmaceutically acceptable nontoxic salts thereof.2. The compound of claim 1 in which R is hydrogen and R₁ is hydrogen ormethyl.
 3. The compound of claim 2 in which R and R₁ are hydrogen and R₂is phenyl.
 4. The compound of claim 3 in which the salt form is thehydrobromide.
 5. A pharmaceutical composition in dosage unit form havingdopaminergic activity comprising an effective therefor but nontoxicquantity of the compound of claim
 1. 6. The method of producingdopaminergic activity in an animal in need of such activity whichcomprises administering internally a nontoxic sufficient amount of thecompound of claim 1.